rs121909541

Variant names:

• chr14-20693772-A-G
• rs121909541
• NM_001097577.3:c.208A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_001097577.3(ANG):​c.208A>G​(p.Ile70Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,614,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (0 hom.)
• Consequence: ANG NM_001097577.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:7
• Conservation: PhyloP100: 0.228
• Publications: 15 publications found

Genes affected

ANG (HGNC:483): (angiogenin) The protein encoded by this gene is a member of the RNase A superfamily though it has relatively weak ribonucleolytic activity. This protein is a potent mediator of new blood vessel formation and thus, in addition to the name RNase5, is commonly called angiogenin. This protein induces angiogenesis after binding to actin on the surface of endothelial cells. This protein also accumulates at the nucleolus where it stimulates ribosomal transcription. Under stress conditions this protein translocates to the cytosol where it hydrolyzes cellular tRNAs and influences protein synthesis. A signal peptide is cleaved from the precursor protein to produce a mature protein which contains a nuclear localization signal, a cell binding motif, and a catalytic domain. This protein has been shown to be both neurotrophic and neuroprotective and the mature protein has antimicrobial activity against some bacteria and fungi, including S. pneumoniae and C. albicans. Due to its effect on rRNA production and angiogenesis this gene plays important roles in cell growth and tumor progression. Mutations in this gene are associated with progression of amyotrophic lateral sclerosis (ALS). This gene and the neighboring RNase4 gene share promoters and 5' exons though each gene then splices to a distinct 3' exon containing the complete coding region of each gene. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2020]

RNASE4 (HGNC:10047): (ribonuclease A family member 4) The protein encoded by this gene belongs to the pancreatic ribonuclease family. It plays an important role in mRNA cleavage and has marked specificity towards the 3' side of uridine nucleotides. Alternative splicing results in four transcript variants encoding the same protein. This gene and the gene that encodes angiogenin share promoters and 5' exons. Each gene splices to a unique downstream exon that contains its complete coding region. [provided by RefSeq, Aug 2013]

ENSG00000259171 (HGNC:):

EGILA (HGNC:54482): (EGFR interacting lncRNA)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001097577.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.12110469).
• BP6: Variant 14-20693772-A-G is Benign according to our data. Variant chr14-20693772-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18079.
• BS2: High AC in GnomAd4 at 109 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001097577.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANG	NM_001097577.3	MANE Select	c.208A>G	p.Ile70Val	missense	Exon 2 of 2	NP_001091046.1	P03950
	RNASE4	NM_002937.5	MANE Select	c.-17-5583A>G		intron	N/A	NP_002928.1	P34096
	ANG	NM_001145.4		c.208A>G	p.Ile70Val	missense	Exon 2 of 2	NP_001136.1	P03950

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANG	ENST00000397990.5	TSL:1 MANE Select	c.208A>G	p.Ile70Val	missense	Exon 2 of 2	ENSP00000381077.4	P03950
	ANG	ENST00000336811.10	TSL:1	c.208A>G	p.Ile70Val	missense	Exon 2 of 2	ENSP00000336762.6	P03950
	RNASE4	ENST00000555835.3	TSL:1 MANE Select	c.-17-5583A>G		intron	N/A	ENSP00000452245.1	P34096

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000732 AC: 184 AN: 251494 AF XY: 0.000817

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000688 AC: 1006 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.000711 AC XY: 517 AN XY: 727248

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86258

European-Finnish (FIN) AF: 0.00150 AC: 80 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000724 AC: 805 AN: 1112012

Other (OTH) AF: 0.000712 AC: 43 AN: 60396

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000738 AC XY: 55 AN XY: 74506

African (AFR) AF: 0.000120 AC: 5 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000935 Hom.: 2

Bravo AF: 0.000597

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000610 AC: 74

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
1	1	1	Amyotrophic lateral sclerosis type 9 (3)
-	-	1	ANG-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	7.9
DANN	Benign	0.51
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.85	L
PhyloP100		0.23
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.48	N
REVEL	Uncertain	0.59
Sift	Benign	0.26	T
Sift4G	Benign	0.30	T
Polyphen		0.25	B
Vest4		0.10
MVP		0.74
MPC		0.19
ClinPred		0.0097	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.81
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121909541; hg19: chr14-21161931; COSMIC: COSV100390994;